Over the last decade, tryptophan catabolism has been firmly established as a powerful mechanism of innate and adaptive immune tolerance. The catabolism of tryptophan is a central pathway maintaining homeostasis by preventing autoimmunity or immunopathology that would result from uncontrolled and overreacting immune responses. This is driven by the key and rate-limiting enzymes indoleamine-2,3-dioxygenase 1 (IDO1) and tryptophan-2,3-dioxygenase 2 (TDO), resulting in local depletion of tryptophan, while tryptophan catabolites accumulate, including kynurenine and its derivatives, depending on the presence of downstream enzymes in the kynurenine pathway. These metabolic modifications result in a local microenvironment that is profoundly immunosuppressive, as a result of various mechanisms whose respective role remains incompletely characterized. Drugs targeting this pathway, specifically IDO1, are already in clinical trials with the aim at reverting cancer-induced immunosuppression. Recent studies have demonstrated favorable pharmacokinetics profiles for first-generation (Indoximod NLG8189) and second-generation IDO1 inhibitors (INCB024360 and NLG919). Targeting tryptophan catabolism in combination with additional methods of therapy may improve efficacy of cancer immunotherapy. These methods include, but are not limited to vaccination, adoptive cellular therapy, checkpoint inhibitor blockade, and cyclooxygenase-2 (COX2) inhibition. Over the last decade, there has been a considerable increase in our understanding of the regulation and downstream mediators of tryptophan metabolism. This detailed understanding will expand opportunities to interfere with the pathway therapeutically on multiple levels. The object of this chapter is to highlight current and past key findings that implicate tryptophan catabolism as an important mediator of cancer immunity and discuss the development of multiple therapeutic targets.